Cardiac function and energetics in mice with combined genetic augmentation of creatine and creatine kinase activity.

Improving energy provision in the failing heart by augmenting the creatine kinase (CK) system is a desirable therapeutic target. However, over-expression of the creatine transporter (CrT-OE) has shown that very high creatine levels result in cardiac hypertrophy and dysfunction. We hypothesise this is due to insufficient endogenous CK activity to maintain thermodynamically favourable metabolite ratios. If correct, then double transgenic mice (dTg) overexpressing both CrT and the muscle isoform of CK (CKM-OE) would rescue the adverse phenotype. In Study 1, overexpressing lines were crossed and cardiac function assessed by invasive haemodynamics and echocardiography. This demonstrated that CKM-OE was safe, but too few hearts had creatine in the toxic range. In Study 2, a novel CrT-OE line was generated with higher, homogeneous, creatine levels and phenotyped as before. Myocardial creatine was 4-fold higher in CrT-OE and dTg hearts compared to wildtype and was associated with hypertrophy and contractile dysfunction. The inability of dTg hearts to rescue this phenotype was attributed to downregulation of CK activity, as occurs in the failing heart. Nevertheless, combining both studies in a linear regression analysis suggests a modest positive effect of CKM over a range of creatine concentrations. In conclusion, we confirm that moderate elevation of creatine is well tolerated, but very high levels are detrimental. Correlation analysis lends support to the theory that this may be a consequence of limited CK activity. Future studies should focus on preventing CKM downregulation to unlock the potential synergy of augmenting both creatine and CK in the heart.

Cardioprotective effect of intradialytic exercise on left atrial mechanics.

Left atrial (LA) function plays a pivotal role in cardiac performance by modulating left ventricular (LV) function. Impairments in LV function are commonly reported during hemodialysis (HD), but available data describing changes in LA function are limited. There is growing evidence of the cardioprotective effect of intradialytic exercise (IDE) on LV function, but studies analyzing its effect on LA function are scarce. Our aim was to evaluate whether IDE can limit the severity of HD-induced impairment in LA myocardial function. In this prospective, open-label, two-center randomized crossover trial, 56 stable individuals receiving HD participated in 2 HD sessions in random order: standard HD and a session incorporating 30 min of aerobic exercise. LA and LV global longitudinal strains (GLSs) were obtained before and at peak stress of HD (i.e., 30 min before the HD ending). IDE totally eradicated the decline in LA reservoir strain observed during HD (estimated difference: 3.1%, 95% confidence interval: 0.4/5.8, P = 0.02), whereas it did not affect the other components of LA mechanics. A similar result favoring IDE intervention was also demonstrated on GLS changes over the HD procedure (P < 0.001). Between-session differences of changes in GLS and LA reservoir strain were correlated (r = -0.32, P = 0.03). The cardioprotective effect of IDE disappeared in patients with LA enlargement (i.e., LA volume index >34 mL/m2). In conclusion, even a short duration of IDE at moderate intensity is effective in preventing HD-associated decline in LA reservoir function. Further research is needed to explore the long-term benefits of IDE on LA function.NEW & NOTEWORTHY A single bout of intradialytic exercise (IDE) at moderate intensity can prevent the hemodialysis-associated decline in left atrial (LA) function. This was partially explained by the relative preservation of left ventricular systolic function with IDE. Benefits of IDE on LA function were lost in patients with LA dilation. Further studies are needed to explore the mechanisms behind IDE-induced cardioprotection and evaluate the clinical impacts of the repetitive cardioprotective effects of IDE on LA function.

Two-dimensional speckle tracking echocardiography in fetuses with critical aortic stenosis before and after fetal aortic valvuloplasty.

BACKGROUND: Critical aortic stenosis (AS) in fetuses may progress to hypoplastic left heart syndrome (HLHS) with need for postnatal single ventricular (SV) palliation. Fetal aortic valvuloplasty (FAV) is performed to achieve postnatal biventricular (BV) circulation. However, the impact of FAV on fetal myocardial function is difficult to measure. Prediction of postnatal circulatory status and, therefore, counseling is challenging. METHODS: Retrospective study of fetuses with critical AS who underwent FAV. Global Longitudinal Peak Systolic Strain (GLPSS) of the left ventricle (LV) and right ventricle (RV) were retrospectively analyzed before and after intervention. Fisher's Exact Test and Mann-Whitney-U Test were used for univariant statistical analysis. RESULTS: 23 fetuses with critical AS were included. After intervention fetuses demonstrated more negative LV-GLPSS mean values post- vs. pre-intervention (- 5.36% vs. - 1.57%; p < 0.05). RV-GLPSS was decreased in all fetuses, there was no peri-interventional change. 20 fetuses were born alive. Postnatally, 10 had BV and 10 SV circulation. Improved post-interventional LV-GLPSS strain values correlated with BV outcome (p < 0.05). Pre-interventional continuous LV-GLPSS values correlated with postnatal SV vs. BV outcome (p < 0.05). CONCLUSION: In some fetuses, LV myocardial function assessed by speckle tracking echocardiography (STE) improves after FAV. Improved post-interventional LV-GLPSS correlates with biventricular postnatal outcome. Furthermore, pre-interventional LV- and RV-GLPSS correlate with postnatal outcome. Further studies are needed to asses, if pre-interventional STE parameters might predict which fetuses will benefit from FAV with postnatal BV circulation.

Valvular heart disease: shifting the focus to the myocardium.

Adverse cardiac remodelling is the main determinant of patient prognosis in degenerative valvular heart disease (VHD). However, to give an indication for valvular intervention, current guidelines include parameters of cardiac chamber dilatation or function which are subject to variability, do not directly reflect myocardial structural changes, and, more importantly, seem to be not sensitive enough in depicting early signs of myocardial dysfunction before irreversible myocardial damage has occurred. To avoid irreversible myocardial dysfunction, novel biomarkers are advocated to help refining indications for intervention and risk stratification. Advanced echocardiographic modalities, including strain analysis, and magnetic resonance imaging have shown to be promising in providing new tools to depict the important switch from adaptive to maladaptive myocardial changes in response to severe VHD. This review, therefore, summarizes the current available evidence on the role of these new imaging biomarkers in degenerative VHD, aiming at shifting the clinical perspective from a valve-centred to a myocardium-focused approach for patient management and therapeutic decision-making.

Comparison of different porcine models simulating myocardial cold ischemia of pediatric donor hearts.

BACKGROUND: Our team previously identified a stem cell-derived cardioprotective additive that can be added to standard cardioplegia to extend myocardial viability during prolonged myocardial cold ischemic time (CIT) in rodent models. The purpose of this study was to utilize a porcine model to compare in-vivo versus ex-vivo porcine simulation of CIT that accompanies cardiac transplantation in humans, in order to determine an optimal method for translation of our studies to larger animals. METHODS: Eight 39-55 kg Yorkshire X pigs were randomly assigned to either in-vivo or ex-vivo simulation. After administration of general anesthesia and endotracheal intubation, baseline measurement of left ventricular performance was obtained via transesophageal echocardiography (TEE). After midline sternotomy and heparin administration, the aorta was cross-clamped and two liters of HTK-Custodiol were introduced via the aortic root. The in-vivo method utilized cold ischemic heart storage in the chest cavity while supporting the experimental animal with cardiopulmonary bypass (CPB). The ex-vivo method involved standard cardiac procurement, cold ischemic storage outside of the body, and subsequent cardiac reperfusion utilizing cardiac reanimation in a Langendorff heart perfusion mode. After CIT, measurements of post-ischemic left ventricular performance were obtained via echocardiography. Results are presented as: Mean ± Standard Deviation (Median, Minimum-Maximum). RESULTS: Weight (kilograms) was similar in the in-vivo group and the ex-vivo group: 44 ± 1.8 (44, 42-46) versus 44 ± 5.1 (43.5, 39-51), respectively. Cold ischemic time (minutes) was longer in the ex-vivo group: 360 ± 0 (360, 360-360) versus 141 ± 26.7 (149, 102-163). Temperature (degrees Celsius) was colder in the ex-vivo group: 8 ± 0 (8, 8-8) versus 16.5 ± 4.2 (16, 12-16).In the in-vivo group, baseline ejection fraction and ejection fraction after CIT were: 48.25% ± 14.95% (48.5%, 33%-63%) and 41.25% ± 22.32% (41.5%, 20%-62%), respectively. In the ex-vivo group, baseline ejection fraction and ejection fraction after CIT were: 56.4% ± 5.9% (57%, 50%-67%) and 60.4% ± 7.7% (61.5%, 51.9%-67%), respectively. CONCLUSION: The ex-vivo technique is suitable to evaluate cardioplegia additives that may substantially extend myocardial tolerance to cold ischemia.

Clinical Value of Troponin Levels to Cardiac Function and Prognosis in Patients with Fulminant Myocarditis.

Troponin (Tn) is a biomarker related to myocardial necrosis and is elevated in patients with myocarditis. This study aimed to investigate the association between cardiac Tn levels and the course of cardiac function, and prognosis in patients with fulminant myocarditis (FM) receiving percutaneous mechanical circulatory support (MCS).We used data from a multicenter retrospective registry, CHANGE PUMP 2, which included 216 patients with FM who required MCS. Among them, 141 patients whose Tn levels were available were analyzed. The patients were divided into low and high Tn groups according to the median values of TnT and TnI.The median age was 54 years, and 59.6% were male. The TnT and TnI on day 1 (at MCS initiation) were 3.8 (1.4-10.0) and 21.4 (8.4-68.8) ng/mL. While the left ventricular ejection fraction (LVEF) was similar on day 1 (25.0% versus 24.5%), the low Tn group showed better LVEF improvement on day 7 than the high Tn group (45.0% versus 25.3%, P < 0.001). LVEF at 1 year after admission was higher in the low Tn group (65.0% versus 59.7%, P = 0.039). The low Tn group had a better 90-day composite endpoint in death, durable left ventricular assist device implantation, and heart transplantation compared to the high Tn group (hazard ratio 0.47, 95% CI 0.23-0.95).Tn levels were associated with short- and long-term cardiac recovery and adverse outcomes in patients with FM receiving MCS due to cardiogenic shock.

Cardiac rehabilitation in heart failure with severely reduced ejection fraction: effects on mortality.

Thirty years ago, patients with low ejection fraction (EF) have often been excluded from rehabilitation programs due to concern about possibility of sudden death or other adverse cardiovascular events during exercise sessions. Recent studies have highlighted the fact that cardiac rehabilitation could improve exercise capacity, cardiac function, and health-related quality of life in congestive heart failure patients. This encouraged us to write a review article and update our latest knowledge about the outcome of rehabilitation program in patients with severely depressed cardiac function. We were particularly interested in effect of cardiac rehabilitation on exercise capacity, quality of life, vascular effects, neuro-hormonal changes, and mortality. We also conducted a mini-systematic review and meta-analysis on randomized controlled trials comparing exercise training with usual care in patients with severely reduced left ventricular ejection fraction, for the mortality subsection to obtain precise estimates of overall treatment benefit on mortality. It is our privilege to submit our manuscript for possible publication in your prestigious journal.

Myocardial fat accumulation is associated with cardiac dysfunction in patients with type 2 diabetes, especially in elderly or female patients: a retrospective observational study.

BACKGROUND: Ectopic fat is fat that accumulates in or around specific organs or compartments of the body including myocardium. The clinical features of type 2 diabetes patients with high fat accumulation in the myocardium remain unknown. Moreover, little is known about the influence of myocardial fat accumulation in type 2 diabetes on coronary artery disease and cardiac dysfunction. We aimed to clarify the clinical features, including cardiac functions, of type 2 diabetes patients with myocardial fat accumulation. METHODS: We retrospectively enrolled type 2 diabetes patients who underwent ECG-gated coronary computed tomography angiography (CCTA) and abdominal computed tomography (CT) scan examinations within 1 year of CCTA from January 2000 to March 2021. High fat accumulation in the myocardium was defined as the low mean myocardial CT value of three regions of interest, and the associations between CT values and clinical characteristics or cardiac functions were assessed. RESULTS: In total, 124 patients were enrolled (72 males and 52 females). The mean age was 66.6 years, the mean BMI was 26.2 kg/m2, the mean ejection fraction (EF) was 67.6%, and the mean myocardial CT value was 47.7 Hounsfield unit. A significant positive correlation was found between myocardial CT value and EF (r = 0.3644, p = 0.0004). The multiple regression analyses also showed that myocardial CT value was independently associated with EF (estimate, 0.304; 95% confidence interval (CI) 0.092 to 0.517; p = 0.0056). Myocardial CT value showed significant negative correlations with BMI, visceral fat area and subcutaneous fat area (r = - 0.1923, - 0.2654, and -0.3569, respectively, p < 0.05). In patients who were ≥ 65 years or female, myocardial CT value showed significant positive correlations with not only EF (r = 0.3542 and 0.4085, respectively, p < 0.01) but also early lateral annular tissue Doppler velocity (Lat e') (r = 0.5148 and 0.5361, respectively, p < 0.05). The multiple regression analyses showed that myocardial CT value was independently associated with EF and Lat e' in these subgroups (p < 0.05). CONCLUSIONS: Patients with type 2 diabetes, especially in elderly or female patients, who had more myocardial fat had more severe left ventricular systolic and diastolic dysfunctions. Reducing myocardial fat accumulation may be a therapeutic target for type 2 diabetes patients.

Synergistic effect on cardiac energetics by targeting the creatine kinase system: in vivo application of high-resolution 31P-CMRS in the mouse.

BACKGROUND: Phosphorus cardiovascular magnetic resonance spectroscopy (31P-CMRS) has emerged as an important tool for the preclinical assessment of myocardial energetics in vivo. However, the high rate and diminutive size of the mouse heart is a challenge, resulting in low resolution and poor signal-to-noise. Here we describe a refined high-resolution 31P-CMRS technique and apply it to a novel double transgenic mouse (dTg) with elevated myocardial creatine and creatine kinase (CK) activity. We hypothesised a synergistic effect to augment energetic status, evidenced by an increase in the ratio of phosphocreatine-to-adenosine-triphosphate (PCr/ATP). METHODS AND RESULTS: Single transgenic Creatine Transporter overexpressing (CrT-OE, n = 7) and dTg mice (CrT-OE and CK, n = 6) mice were anaesthetised with isoflurane to acquire 31P-CMRS measurements of the left ventricle (LV) utilising a two-dimensional (2D), threefold under-sampled density-weighted chemical shift imaging (2D-CSI) sequence, which provided high-resolution data with nominal voxel size of 8.5 µl within 70 min. (1H-) cine-CMR data for cardiac function assessment were obtained in the same imaging session. Under a separate examination, mice received invasive haemodynamic assessment, after which tissue was collected for biochemical analysis. Myocardial creatine levels were elevated in all mouse hearts, but only dTg exhibited significantly elevated CK activity, resulting in a 51% higher PCr/ATP ratio in heart (3.01 ± 0.96 vs. 2.04 ± 0.57-mean ± SD; dTg vs. CrT-OE), that was absent from adjacent skeletal muscle. No significant differences were observed for any parameters of LV structure and function, confirming that augmentation of CK activity does not have unforeseen consequences for the heart. CONCLUSIONS: We have developed an improved 31P-CMRS methodology for the in vivo assessment of energetics in the murine heart which enabled high-resolution imaging within acceptable scan times. Mice over-expressing both creatine and CK in the heart exhibited a synergistic elevation in PCr/ATP that can now be tested for therapeutic potential in models of chronic heart failure.

Major impact of vitamin D3 deficiency and supplementation on left ventricular torsional mechanics during dobutamine stress in uncomplicated type 2 diabetes.

BACKGROUND AND AIMS: Hypovitaminosis D is associated with the risk of diabetic complications. Its role in diabetic-related cardiac abnormalities remain poorly understood. We aimed therefore to evaluate the effect of vitamin D deficiency and supplementation on early left ventricular (LV) dysfunction in vitamin D deficient patients with uncomplicated T2D. METHODS AND RESULTS: Sixty-three consecutive T2D patients who had a diagnosis of vitamin D3 were prospectively recruited and allocated into 2 groups (25(OH)D < 20 ng/mL: VDD, >20 ng/mL VDND). Twenty-eight of them with 25(OH)D < 20 ng/mL benefited from a 3-month supplementation. At baseline and follow-up, after conventional echocardiography including evaluation of epicardial adipose tissue (EAT), both LV longitudinal (LS) and circumferential (CS) strains and rotation/twist mechanics were evaluated at rest and during dobutamine (DOB) stress. After treatment, T2D patients successfully normalized their 25(OH)D levels. The strongest associations between vitamin D deficiency and supplementation with LV myocardial function were noticed for torsional mechanics indexes under DOB. EAT correlated significantly (p < 0.01) with baseline 25(OH)D and was reduced after supplementation. Significant correlations were obtained between these 2 parameters with twist or apical rotation at baseline (p < 0.01) and between their delta changes at follow-up (p < 0.01) under DOB. Significant improvements in LS and CS (p < 0.05) under DOB were also underlined at follow-up, with major enhancements noticed in the apical region (p < 0.01) of the LV. CONCLUSIONS: This study provides the first evidences of the potential of vitamin D supplementation as an efficient prophylactic strategy to alleviate the progression of myocardial dysfunction in asymptomatic patients with uncomplicated T2D. CLINICALTRIALS: NCT03437421.

Assessment of myocardial function in late preterm and term infants with transient tachypnea of the newborn using tissue Doppler imaging - a pilot observational study.

The aim of this study was to compare conventional and tissue Doppler echocardiography parameters between transient tachypnea of the newborn (TTN) and healthy control infants. This cross sectional pilot observational study was conducted in a level 3 neonatal care unit of India. Consecutively born late preterm and term infants (LPTI) with TTN were eligible for enrollment. Control group was selected from healthy LPTI. Conventional and tissue Doppler (myocardial velocities, myocardial performance index (MPI)) echocardiography was done within first 12 h (D1) and 48-72 h (D3) of life. Conventional echocardiography parameters were fractional shortening (FS), ejection fraction (EF), ventricular output, E/A ratio, fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), pulmonary artery systolic pressure (PASP), and pulmonary artery acceleration to ejection time ratio (PATET). Baseline characteristics and echocardiography images were compared between TTN and control groups. Out of 60 infants enrolled, 34 from TTN and 20 from control group were finally analyzed. Mean (SD) gestational age and birth weight of the study population was 366/7(1.8) weeks and 2398(376) g respectively. Left ventricular (LV) parameters were similar between both groups. On D1, right ventricular (RV)e' was smaller (6.42(1) cm/s vs. 7.68(1.68) cm/s, p 0.022), and E/e' (7.79(1.51) vs. 6.08(2.59), p 0.037) was larger in TTN group, indicating RV diastolic dysfunction. RV MPI (0.61(0.11) vs. 0.44(0.12), p < 0.001) was also larger, signifying RV global myocardial dysfunction. Similar findings were observed on D3. PATET was lower in TTN group on both D1 (0.34 (0.05) vs. 0.42 (0.05), p < 0.001) and D3 (0.38 (0.05) vs. 0.43 (0.02), p 0.004) suggesting persistently raised pulmonary arterial pressure, although only 2 infants developed pulmonary hypertension identified by standard echocardiography.   Conclusion: Myocardial tissue Doppler imaging of TTN infants revealed occult right ventricular diastolic dysfunction secondary to persistently raised pulmonary arterial pressure. What is Known: •Transient tachypnea of the newborn may be associated with pulmonary arterial hypertension. What is New: •Tissue Doppler imaging in infants with transient tachypnea of the newborn revealed occult right ventricular diastolic dysfunction secondary to raised pulmonary arterial pressure, not detected by standard echocardiography.

Segmental and global myocardial work in hypertensive patients with different left ventricular geometry.

BACKGROUND: Myocardial work acquired by echocardiography has emerged as a novel method to evaluate myocardial function. We investigated global and segmental myocardial work in hypertension (HT) among patients with different patterns of left ventricular (LV) geometry in order to analyze the contribution of segmental myocardial work to global myocardial work. METHODS AND RESULTS: One hundred twenty-five patients with HT were divided into 4 groups: normal geometry (NG), concentric remodeling (CR), concentric hypertrophy (CH) and eccentric hypertrophy (EH). Longitudinal strain (LS) and the following indices were obtained by echocardiography: myocardial work index (MWI), myocardial constructive work (MCW), myocardial wasted work (MWW), and myocardial work efficiency (MWE). The global longitudinal strain (GLS) decreased gradually among the groups: NG, CR, CH and EH (P < 0.001). Global MWI (GWI) and global MCW (GCW) did not change across the different LV remodeling groups. Global MWW (GWW) increased and global MWE (GWE) decreased in both CH and EH group (P < 0.001). The LS of basal and middle regions reduced gradually in all HT subgroups, while apical LS decreased only in the CH and EH groups (P < 0.001). Basal MWI and MCW decreased in the CH and EH groups (P = 0.025, 0.007, respectively). Apical MWI and MCW increased in the NG and CR groups (P = 0.015, 0.044, respectively), with a decreasing trend in the CH and EH groups. All segmental MWW elevated and MWE reduced significantly in the CH and EH groups (P < 0.001). Univariate and multivariate logistic regression analyses demonstrated a significant association between left atrial volume index (LAVI), GLS, GWE and LV hypertrophy. At the receiver operating characteristic (ROC) analysis, optimal cutoff values of GLS, Apical LS, GWE and Apical MWE discriminating LV hypertrophy were 0.9072, 0.8049, 0.8325 and 0.7414, respectively. CONCLUSION: Apical myocardial work increases in the early stages of LV remodeling, likely as a compensatory mechanism to maintain normal global myocardial work. Segmental myocardial work analysis offers a reliable means to explore the distribution of myocardial impairment in hypertensive patients at different LV remodeling stages.

Assessment of myocardial function in infants conceived by assisted reproductive technologies using deformation imaging over the first year of age: A cohort study.

BACKGROUND AND AIM: There is emerging evidence of cardiovascular remodeling and functional impairment in individuals conceived via Assisted Reproductive Technologies (ART). The aim of this study was to serially assess myocardial function and pulmonary hemodynamic measurements in infants conceived via ART over the first year of age and to compare them to a cohort of spontaneously conceived controls. METHODS: This was a prospective, observational study. Echocardiography was performed at Day 2, 6 months and 1 year of age. Biventricular function was assessed by deformation analysis. Pulmonary artery acceleration time (PAAT) and left ventricular (LV) eccentricity index (LVEI) provided surrogate measures of pulmonary vascular resistance (PVR). RESULTS: Fifty infants conceived via ART were compared to 50 spontaneously conceived controls. There were no differences in baseline infant demographics between the two groups. At 1 year of age right ventricular (RV) basal and RV mid cavity diameters were higher in the ART group. PAATi was lower and LVEI higher in the ART group at 6 months and 1 year. In the ART group, LV global longitudinal strain, LV systolic strain rate, LV early diastolic strain rate and RV free wall strain were lower on Day 2, 6 months, and 1 year of age in comparison to the control group (all p < .05). Within the ART group, on linear regression, maternal age, the type of ART treatment or egg characteristics did not influence PAAT or deformation measurements. CONCLUSION: Our findings suggest that greater cardiovascular surveillance of ART conceived infants may be warranted.

The serial changes in myocardial functions after paediatric haematopoietic stem cell transplantation.

The aim of this study is to evaluate the changes in myocardial functions in children who underwent haematopoietic stem cell transplantation along with associated chemotherapy. Additionally, we evaluated the effect of baseline echocardiographic parameters on mortality. We evaluated 39 patients (mean age 7.4 years) who underwent haematopoietic stem cell transplantation owing to non-malignant disease. The control group included 39 healthy children who had normal cardiac findings. The myocardial functions were evaluated in all subjects by conventional echocardiography and tissue Doppler echocardiography before haematopoietic stem cell transplantation and in the 1st, 3rd, 6th, and 12th month after haematopoietic stem cell transplantation. All patients had normal left ventricular ejection fraction before haematopoietic stem cell transplantation, except one case. Before haematopoietic stem cell transplantation, the patient group had significantly greater mean pulmonary artery pressure and lower tricuspid valve annular plane excursion rate. Baseline E' velocities for mitral lateral annuli, septum, and tricuspid lateral annuli were lower in the patient group than the control group. The E' velocities for the left ventricle decreased in the patient group after haematopoietic stem cell transplantation, and then returned to baseline levels at the 6 months. E' and S' velocities for tricuspid lateral annuli also decreased after haematopoietic stem cell transplantation and were still depressed in the first year after haematopoietic stem cell transplantation. Baseline E' velocity for septum was significantly lower in patients who died after haematopoietic stem cell transplantation than patients who survived (p = 0.009). Subclinical impairment in both ventricular functions was observed after haematopoietic stem cell transplantation and the right ventricular functions were affected for longer periods than left ventricle after haematopoietic stem cell transplantation. The myocardial functions should be monitored after the first year of haematopoietic stem cell transplantation.

Effect of SARS-CoV-2 mRNA-Vaccine on the Induction of Myocarditis in Different Murine Animal Models.

In the course of the SARS-CoV-2 pandemic, vaccination safety and risk factors of SARS-CoV-2 mRNA-vaccines were under consideration after case reports of vaccine-related side effects, such as myocarditis, which were mostly described in young men. However, there is almost no data on the risk and safety of vaccination, especially in patients who are already diagnosed with acute/chronic (autoimmune) myocarditis from other causes, such as viral infections, or as a side effect of medication and treatment. Thus, the risk and safety of these vaccines, in combination with other therapies that could induce myocarditis (e.g., immune checkpoint inhibitor (ICI) therapy), are still poorly assessable. Therefore, vaccine safety, with respect to worsening myocardial inflammation and myocardial function, was studied in an animal model of experimentally induced autoimmune myocarditis. Furthermore, it is known that ICI treatment (e.g., antibodies (abs) against PD-1, PD-L1, and CTLA-4, or a combination of those) plays an important role in the treatment of oncological patients. However, it is also known that treatment with ICIs can induce severe, life-threatening myocarditis in some patients. Genetically different A/J (most susceptible strain) and C57BL/6 (resistant strain) mice, with diverse susceptibilities for induction of experimental autoimmune myocarditis (EAM) at various age and gender, were vaccinated twice with SARS-CoV-2 mRNA-vaccine. In an additional A/J group, an autoimmune myocarditis was induced. In regard to ICIs, we tested the safety of SARS-CoV-2 vaccination in PD-1-/- mice alone, and in combination with CTLA-4 abs. Our results showed no adverse effects related to inflammation and heart function after mRNA-vaccination, independent of age, gender, and in different mouse strains susceptible for induction of experimental myocarditis. Moreover, there was no worsening effect on inflammation and cardiac function when EAM in susceptible mice was induced. However, in the experiments with vaccination and ICI treatment, we observed, in some mice, low elevation of cardiac troponins in sera, and low scores of myocardial inflammation. In sum, mRNA-vaccines are safe in a model of experimentally induced autoimmune myocarditis, but patients undergoing ICI therapy should be closely monitored when vaccinated.

Echocardiographic Study of Left Ventricular Pressure-Strain Loop in Evaluating Changes in Left Ventricular Myocardial Work in Breast Cancer Patients After Chemotherapy.

This study aimed to evaluate the changes in the left ventricular (LV) myocardial work (MW) in breast cancer patients following chemotherapy by left ventricular pressure-strain loop (LVPSL).A total of 50 patients with newly breast cancer undergoing postoperative adjuvant chemotherapy containing anthracycline were selected. Echocardiography was performed before the treatment (T0), the second (T2) and fourth (T4) cycles of chemotherapy, and 3 (P3 m) and 6 (P6 m) months after the end of chemotherapy. The standard dynamic images of the required sections were collected. After off-line analysis, the routine, global myocardial strain, and global MW parameters were obtained, and the average regional MW index (RMWI) and regional MW efficiency (RMWE) at three levels of LV were calculated.Compared with those at T0 and T2, the global work index (GWI), global constructive work (GCW), global work efficiency (GWE), and global longitudinal strain (GLS) gradually decreased and global wasted work (GWW) gradually increased at T4, P0, and P6 m. The mean RMWI and RMWE of the three levels of LV exhibited a gradually decreasing trend at T4, P0, and P6 m compared with those at T0 and T2. The GWI, GCW, GWE, mean RMWI, and RMWE (basal, medial, and apical) were negatively correlated with the GLS (r = -0.76, -0.66, -0.67, -0.76, -0.77, -0.66, -0.67, -0.59, and -0.61, respectively), whereas the GWW was positively correlated with the GLS (r = 0.55).The mean RMWI and RMWE are effective parameters to reflect the cardiotoxicity of LV, and LVPSL has certain value in the evaluation of the left ventricular myocardial work (LVMW) during anthracycline treatment and follow-up in breast cancer patients.

Relationship of Microvascular Obstruction with Global and Regional Myocardial Function Determined by Cardiac Magnetic Resonance after ST-Segment Elevation Myocardial Infarction.

Objective To investigate the impact of microvascular obstruction (MVO) on the global and regional myocardial function by cardiac magnetic resonance feature-tracking (CMR-FT) in ST-segment-elevation myocardial infarction (STEMI) patients after percutaneous coronary intervention.Methods Consecutive acute STEMI patients who underwent cardiac magnetic resonance imaging 1 - 7 days after successful reperfusion by percutaneous coronary intervention treatment were included in this retrospective study. Based on the presence or absence of MVO on late gadolinium enhancement images, patients were divided into groups with MVO and without MVO. The infarct zone, adjacent zone, and remote zone were determined based on a myocardial 16-segment model. The radial strain (RS), circumferential strain (CS), and longitudinal strain (LS) of the global left ventricle (LV) and the infarct, adjacent, and remote zones were measured by CMR-FT from cine images and compared between patients with and without MVO using independent-samples t-test. Logistic regression analysis was used to assess the association of MVO with the impaired LV function.Results A total of 157 STEMI patients (mean age 56.66 ± 11.38 years) were enrolled. MVO was detected in 37.58% (59/157) of STEMI patients, and the mean size of MVO was 3.00 ±3.76 mL. Compared with patients without MVO (n =98 ), the MVO group had significantly reduced LV global RS (t= -4.30, P < 0.001), global CS (t= 4.99, P < 0.001), and global LS ( t= 3.51, P = 0.001). The RS and CS of the infarct zone in patients with MVO were significantly reduced (t= -3.38, P = 0.001; t= 2.64, P = 0.01; respectively) and the infarct size was significantly larger (t= 8.37, P < 0.001) than that of patients without MVO. The presence of LV MVO [OR= 4.10, 95%CI: 2.05 - 8.19, P<0.001) and its size [OR=1.38, 95%CI: 1.10-1.72, P=0.01], along with the heart rate and LV infarct size were significantly associated with impaired LV global CS in univariable Logistic regression analysis, while only heart rate (OR=1.08, 95%CI: 1.03 - 1.13, P=0.001) and LV infarct size (OR=1.10, 95%CI: 1.03 - 1.16, P=0.003) were independent influencing factors for the impaired LV global CS in multivariable Logistic regression analysis.Conclusion The infarct size was larger in STEMI patients with MVO, and MVO deteriorates the global and regional LV myocardial function.

Hydrogen sulfide plays a potential alternative for the treatment of metabolic disorders of diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a cardiovascular complication that tends to occur in patients with diabetes, obesity, or insulin resistance, with a higher late mortality rate. Sustained hyperglycemia, increased free fatty acids, or insulin resistance induces metabolic disorders in cardiac tissues and cells, leading to myocardial fibrosis, left ventricular hypertrophy, diastolic and/or systolic dysfunction, and finally develop into congestive heart failure. The close connection between all signaling pathways and the complex pathogenesis of DCM cause difficulties in finding effective targets for the treatment of DCM. It reported that hydrogen sulfide (H2S) could regulate cell energy substrate metabolism, reduce insulin resistance, protect cardiomyocytes, and improve myocardial function by acting on related key proteins such as differentiation cluster 36 (CD36) and glucose transporter 4 (GLUT4). In this article, the relative mechanisms of H2S in alleviating metabolic disorders of DCM were reviewed, and how H2S can better prevent and treat DCM in clinical practice will be discussed.

Functional and structural reverse myocardial remodeling following transcatheter aortic valve replacement: a prospective cardiovascular magnetic resonance study.

BACKGROUND: Since cardiovascular magnetic resonance (CMR) imaging allows comprehensive quantification of both myocardial function and structure we aimed to assess myocardial remodeling processes in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). METHODS: CMR imaging was performed in 40 patients with severe AS before and 1 year after TAVR. Image analyses comprised assessments of myocardial volumes, CMR-feature-tracking based atrial and ventricular strain, myocardial T1 mapping, extracellular volume fraction-based calculation of left ventricular (LV) cellular and matrix volumes, as well as ischemic and non-ischemic late gadolinium enhancement analyses. Moreover, biomarkers including NT-proBNP as well as functional and clinical status were documented. RESULTS: Myocardial function improved 1 year after TAVR: LV ejection fraction (57.9 ± 16.9% to 65.4 ± 14.5%, p = 0.002); LV global longitudinal (- 21.4 ± 8.0% to -25.0 ± 6.4%, p < 0.001) and circumferential strain (- 36.9 ± 14.3% to - 42.6 ± 11.8%, p = 0.001); left atrial reservoir (13.3 ± 6.3% to 17.8 ± 6.7%, p = 0.001), conduit (5.5 ± 3.2% to 8.4 ± 4.6%, p = 0.001) and boosterpump strain (8.2 ± 4.6% to 9.9 ± 4.2%, p = 0.027). This was paralleled by regression of total myocardial volume (90.3 ± 21.0 ml/m2 to 73.5 ± 17.0 ml/m2, p < 0.001) including cellular (55.2 ± 13.2 ml/m2 to 45.3 ± 11.1 ml/m2, p < 0.001) and matrix volumes (20.7 ± 6.1 ml/m2 to 18.8 ± 5.3 ml/m2, p = 0.036). These changes were paralleled by recovery from heart failure (decrease of NYHA class: p < 0.001; declining NT-proBNP levels: 2456 ± 3002 ng/L to 988 ± 1222 ng/L, p = 0.001). CONCLUSION: CMR imaging enables comprehensive detection of myocardial remodeling in patients undergoing TAVR. Regression of LV matrix volume as a surrogate for reversible diffuse myocardial fibrosis is accompanied by increase of myocardial function and recovery from heart failure. Further data are required to define the value of these parameters as therapeutic targets for optimized management of TAVR patients. Trial registration DRKS, DRKS00024479. Registered 10 December 2021-Retrospectively registered, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00024479.

Vitamin D3 Supplementation Alleviates Left Ventricular Dysfunction in a Mouse Model of Diet-Induced Type 2 Diabetes: Potential Involvement of Cardiac Lipotoxicity Modulation.

PURPOSE: To evaluate the effectiveness of vitamin D3 supplementation, in secondary prevention, on cardiac remodeling and function, as well as lipid profile, in a mouse model of diet-induced type 2 diabetes. METHODS: Mice were fed a high fat and sucrose diet for 10 weeks. Afterward, diet was maintained for 15 more weeks and two groups were formed, with and without cholecalciferol supplementation. A control group was fed with normal chow. Glucose homeostasis and cardiac function were assessed at baseline and at the 10th and 24th weeks. Animals were killed at the 10th and 25th weeks for plasma and cardiac sample analysis. Cardiac lipid profile was characterized by LC-MS/MS. RESULTS: After 10 weeks of diet, mice exhibited pre-diabetes, mild left ventricle hypertrophy, and impaired longitudinal strain, but preserved myocardial circumferential as well as global diastolic and systolic cardiac function. After 15 more weeks of diet, animals presented with well-established type 2 diabetes, pathological cardiac hypertrophy, and impaired regional myocardial function. Cholecalciferol supplementation had no effect on glucose homeostasis but improved cardiac remodeling and regional myocardial function. After 25 weeks, non-supplemented mice exhibited increased myocardial levels of ceramides and diacylglycerol, both of which were normalized by vitamin D3 supplementation. CONCLUSION: This work brought to light the beneficial effects of cholecalciferol supplementation, in secondary prevention, on cardiac remodeling and function in a mouse model of diet-induced type 2 diabetes. Those cardioprotective effects may be, at least in part, attributed to the modulation of myocardial levels of lipotoxic species by vitamin D.